Pathologic manifestations of diabetic nephropathy (DN) include glomerular and tubular hypertrophy and matrix protein fibronectin expression. These changes occur concomitant with increased expression of TGFb (transforming growth factor-b) that contributes to the pathogenesis of human and experimental DN. We interrogate the molecular signaling events by which high glucose and TGFb drive the pathologies and provide new potential therapeutic strategies for complications of DN. We have reported that Akt kinase/mTORC1 (mechanistic target of rapamycin complex 1) axis contributes to renal hypertrophy and fibronectin expression in mesangial and proximal tubular epithelial (PTE) cells, and in kidneys of type 1 and type 2 diabetic mice. Recently, a novel longer translational variant of PTEN (phosphatase and tensin homolog deleted in chromosome 10), PTEN-Long, a negative regulator of Akt kinase, has been identified as a secretory and membrane permeable protein. Our preliminary data show markedly reduced levels of PTEN-Long along with increased Akt kinase activity in the kidney cortex of type 1 and type 2 diabetic mice and in high glucose- or TGFb-treated mesangial and PTE cells. Moreover, we show that high glucose and TGFb activate PDGFRb (platelet-derived growth factor-b). We find PDGFRb as a substrate for PTEN-Long; thus downregulation of PTEN-Long results in PDGFRb activation by high glucose and TGFb. Furthermore, in the kidney and in mesangial and PTE cells, we identify Akt-2 as the predominant isotype of Akt kinase that acts downstream of PTEN-Long/PDGFRb. Also, Akt-2 is activated in kidneys of type 1 and type 2 diabetic mice kidneys. We plan to exploit the intrinsic protective function of PTEN-long during the progression of DN. In this proposal, using cultured mesangial and PTE cells and renal tissues from diabetic OVE26 and db/db mice, we will test the hypothesis that hyperglycemia/TGFb-induced inappropriate downregulation of PTEN-Long results in PDGFRb/Akt-2 activation that contributes to renal hypertrophy and matrix expansion in diabetic kidney disease. Probing the novel negative regulatory function of PTEN-Long, we will use it as a therapeutic agent for DN. In the first specific aim, we will determine the role of PTEN-Long in hypertrophy and, fibronectin and PAI-1 (plasminogen-activator inhibitor-1) expression. In the second aim, how PTEN-Long forces activation of PDGFRb to regulate mesangial and PTE cell hypertrophy, and matrix protein expression will be investigated.
In specific aim 3, we will study the contribution of Akt-2 isotype to hypertrophy and fibronectin/PAI-1 expression in response to high glucose and TGFb in mesangial and PTE cells and in diabetic mice kidneys. To address these aims, techniques including immunoblotting, immunoprecipitation, morphometry, immunohistochemistry, transfection of expression vectors and siRNAs, administration of recombinant therapeutic protein and small molecule compound will be employed. Our study will establish a network of interconnections involving PTEN- Long, PDGFRb and Akt-2 for driving DN.
Diabetes is a pandemic, emerging as one of the most prevalent diseases among people aged 20 years and older in the United States. The demographics of veteran population fall in this age group. In those, 25% are afflicted with diabetes. Currently, a significant proportion of VA health care resources are devoted to older veterans, whom constitute over 45% of the patients. The cost of diabetes in the US in 2017 was $327 billion and VA spends $1.5 billion annually. Diabetic nephropathy (DN) is the leading cause of end stage renal disease (ESRD) accounting for 44% new cases each year. Current therapies only delay the progression to ESRD and do not arrest the disease. Therefore, there is urgent need for new therapeutic approaches for DN. This proposal will explore the therapeutic modality of a newly identified translational variant of PTEN (phosphatase and tensin homolog deleted in chromosome 10), PTEN-Long, in rodent models of DN. Also, its role in activation of platelet- derived growth factor receptor-b for progression of DN will be investigated.
|Das, Falguni; Ghosh-Choudhury, Nandini; Lee, Doug Yoon et al. (2018) Akt2 causes TGF?-induced deptor downregulation facilitating mTOR to drive podocyte hypertrophy and matrix protein expression. PLoS One 13:e0207285|
|Shi, Qian; Viswanadhapalli, Suryavathi; Friedrichs, William E et al. (2018) Nox4 is a Target for Tuberin Deficiency Syndrome. Sci Rep 8:3781|
|Das, Falguni; Ghosh-Choudhury, Nandini; Kasinath, Balakuntalam S et al. (2018) Tyrosines-740/751 of PDGFR? contribute to the activation of Akt/Hif1?/TGF? nexus to drive high glucose-induced glomerular mesangial cell hypertrophy. Cell Signal 42:44-53|
|Maity, Soumya; Bera, Amit; Ghosh-Choudhury, Nandini et al. (2018) microRNA-181a downregulates deptor for TGF?-induced glomerular mesangial cell hypertrophy and matrix protein expression. Exp Cell Res 364:5-15|
|Lee, Hak Joo; Lee, Doug Yoon; Mariappan, Meenalakshmi M et al. (2017) Hydrogen sulfide inhibits high glucose-induced NADPH oxidase 4 expression and matrix increase by recruiting inducible nitric oxide synthase in kidney proximal tubular epithelial cells. J Biol Chem 292:5665-5675|
|Das, Falguni; Ghosh-Choudhury, Nandini; Venkatesan, Balachandar et al. (2017) PDGF receptor-? uses Akt/mTORC1 signaling node to promote high glucose-induced renal proximal tubular cell collagen I (?2) expression. Am J Physiol Renal Physiol 313:F291-F307|
|Bera, Amit; Das, Falguni; Ghosh-Choudhury, Nandini et al. (2017) Reciprocal regulation of miR-214 and PTEN by high glucose regulates renal glomerular mesangial and proximal tubular epithelial cell hypertrophy and matrix expansion. Am J Physiol Cell Physiol 313:C430-C447|
|Das, Falguni; Dey, Nirmalya; Bera, Amit et al. (2016) MicroRNA-214 Reduces Insulin-like Growth Factor-1 (IGF-1) Receptor Expression and Downstream mTORC1 Signaling in Renal Carcinoma Cells. J Biol Chem 291:14662-76|
|Sataranatarajan, Kavithalakshmi; Ikeno, Yuji; Bokov, Alex et al. (2016) Rapamycin Increases Mortality in db/db Mice, a Mouse Model of Type 2 Diabetes. J Gerontol A Biol Sci Med Sci 71:850-7|
|Dey, Nirmalya; Bera, Amit; Das, Falguni et al. (2015) High glucose enhances microRNA-26a to activate mTORC1 for mesangial cell hypertrophy and matrix protein expression. Cell Signal 27:1276-85|
Showing the most recent 10 out of 12 publications